Autophagy as a Therapeutic Target in Diabetic Nephropathy

Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. Autophagy is a major catabolic pathway involved in degrading and recycling macromolecules and damaged organelles to maintain intracellular homeostasis. The study of autophagy in mammalian systems is advancing rapidly and has revealed that it is involved in the pathogenesis of various metabolic or age-related diseases. The functional role of autophagy in the kidneys is also currently under intense investigation although, until recently, evidence showing the involvement of autophagy in the pathogenesis of diabetic nephropathy has been limited. We provide a systematic review of autophagy and discuss the therapeutic potential of autophagy in diabetic nephropathy to help future investigations in this field

Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients

WSTĘP. Mikroalbuminuria u chorych na cukrzycę typu 2 jest predyktorem nefropatii cukrzycowej oraz chorób układu sercowo-naczyniowego. Celem niniejszego badania obserwacyjnego była ocena efektu klinicznego redukcji mikroalbuminurii u chorych na cukrzycę typu 2. MATERIAŁ I METODY. W ciągu pierwszych 2 lat badania do projektu włączono 216 chorych na cukrzycę typu 2 z mikroalbuminurią, których obserwowano przez następne 8 lat. Za remisję lub 50-procentowe zmniejszenie mikroalbuminurii przyjęto odpowiednio powrót do wartości prawidłowych lub zmniejszenie poziomu mikroalbuminurii o połowę w porównaniu z poziomem wyjściowym. Analizowano zależność między redukcją poziomu mikroalbuminurii a czasem wystąpienia pierwszych objawów zaburzeń nerkowych lub sercowo-naczyniowych oraz oznaczanym co roku wskaźnikiem estymowanej filtracji kłębuszkowej (eGFR). WYNIKI. W grupie 93 chorych z 50-procentowym zmniejszeniem poziomów mikroalbuminurii odnotowano 12 incydentów nerkowych lub sercowo-naczyniowych w porównaniu z 35 w grupie 123 chorych bez takiej redukcji. Skumulowany wskaźnik częstości wspomnianych powikłań cukrzycy był istotnie mniejszy w grupie chorych z 50-procentową redukcją poziomów mikroalbuminurii. Analiza przy użyciu sumarycznej regresji logistycznej wykazała skorygowane ryzyko powikłań 0,41 (95% CI: 0,15-0,96) u chorych z 50-procentową redukcją mikroalbuminurii. Oznaczany co roku wskaźnik spadku eGFR u tych osób pogarszał się wolniej w porównaniu z grupą bez 50-procentowej redukcji mikroalbuminurii. Podobne dane uzyskano, analizując dane dotyczące okresów remisji. WNIOSKI. W przedstawionym badaniu dowiedziono, że redukcja mikroalbuminurii u chorych na cukrzycę typu 2 istotnie wpływa na zmniejszenie ryzyka powikłań nerkowych i sercowo-naczyniowych cukrzycy.OBJECTIVE. Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS. We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction < 50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS. Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI: 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS. The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction

Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P Conclusions The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease

Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients

Background: The features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality. Methods: This was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48 h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated. Results: We evaluated 192 ARDS patients (median age, 69 years (quartile, 24 years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. ?0.3 mL/kg, p = 0.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWi > 2.8 had a significantly higher incidence of survival than those with Δ-EVLWi ? 2.8 (log-rank test, χ2 = 7.08, p = 0.008). Conclusions: Decrease in EVLWi during the first 48 h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI\u3e30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI\u3e30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN

GW501516, a PPARδ Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFκB Pathway in Mice

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(−). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases

Sneaker Male in Octopus

The copulation of Octopus cyanea was observed in the underwater of Hachijo Island, Central Japan. Firstly, two males pursued a female, and smaller male retreated. Folleowing the start of copulation of large male and female, smaller male started again to approach the mating pair mimicking a female. Three individuals became finally at the state of tranquillity, and reposed over two hours. This behavior of smaller male seems to be a "sneaking", one of alternative reproductive strategies. This behavior seems to be established in association with territerial behavior in octopus